Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl-:9].[Na+].S(=O)(=O)(O)[OH:12].I([O-])(=O)(=O)=O.[Na+]>C(#N)C.O>[C:3]1([CH:2]([OH:12])[CH2:1][Cl:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [Cl-]
Reactant: O=S(=O)(O)O
Reactant: C=Cc1ccccc1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: OC(CCl)c1ccccc1
Temperature: 70 °C
Yield: 95 %

Procedure:
Styrene (1 mmol) was treated with sodium chloride (1.2 mmol) in acetonitrile: water (2:1, 6 ml). 20% Sulfuric acid (5 ml) and sodium periodate (20 mol %) was added to the reaction mixture. The mixture was heated at 70° C. under inert atmosphere for 18 h. The product was purified by column chromatography to give 1-phenyl-2-chloroethanol (95%).
Reaction SMILES: Br[C:2]1[S:6][C:5]2[C:7]3[S:8][C:9](Br)=[CH:10][C:11]=3[C:12]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:4]=2[CH:3]=1.C(O[CH2:28][CH3:29])C>>[C:4]1([C:2]2[S:6][C:5]3[C:7]4[S:8][C:9]([C:29]5[CH:28]=[CH:17][CH:16]=[CH:15][CH:14]=5)=[CH:10][C:11]=4[C:12]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:4]=3[CH:3]=2)[CH:13]=[CH:12][CH:11]=[CH:7][CH:5]=1
Reactant: CCCCCc1c(CCCCC)c2cc(Br)sc2c2sc(Br)cc12
Reactant: CCOCC
Product: CCCCCc1c(CCCCC)c2cc(-c3ccccc3)sc2c2sc(-c3ccccc3)cc12
Yield: 67 %

Procedure:
A reaction was carried out in the same manner as in Example 11, except that 2,7-dibromo-4,5-di(n-pentyl)benzo[2,1-b:3,4-b′]dithiophene (124.9 mg (0.26 mmol)) was used instead of 2,7-dibromo-4,5-di(n-propyl)benzo[2,1-b:3,4-b′]dithiophene. The post-reaction solution was charged with diethyl ether (about 20 mL), and the resultant solution was then washed with water. Subsequently, the organic layer was dried over sodium sulfate, and then filtered. The solvent was removed from the filtrate by distillation, and then the remaining solid was purified by thin-layer column chromatography using hexane as a developing solvent to obtain the target product 2,7-diphenyl-4,5-di(n-pentyl)benzo[2,1-b:3,4-b′]dithiophene as a yellow solid (83.8 mg, 67% yield). The obtained target product 1H-NMR and HRMS measurement results were as follows.
Reaction SMILES: [CH3:1][Sn:2](Cl)([CH3:4])[CH3:3].[C:6]1([CH3:14])[CH:11]=[CH:10][C:9]([Mg]Br)=[CH:8][CH:7]=1.[Cl-].[NH4+]>C1COCC1>[CH3:1][Sn:2]([CH3:4])([CH3:3])[C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:14])[CH:11]=1
Reactant: C[Sn](C)(C)Cl
Reactant: Cc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cccc([Sn](C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 21.5 g (100 mmol) trimethyltin chloride in 500 mL THF at -35° C. was added 113 mL (113 mmol) 1.0M p-tolylmagnesium bromide over 3 minutes. The mixture was allowed to warm to RT and stir for 1 hour after which time was added saturated aqueous ammonium chloride. The mixture was extracted three times with ether. The combined organic material was washed with brine, was dried over MgSO4, was stripped of solvent in vacuo, then was distilled at 0.1 Torr with the title compound distilling between 66°-74° C. The bitolyl remaining in the still pot crystallized upon cooling. The title compound was isolated as a clear, shiny liquid, 25.4 (92% yield).
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[CH:2]=[CH2:3].Br[C:14]1[CH:23]=[CH:22][C:21]2[NH:20][C:19](=[O:24])[N:18]3[C:25](=[O:35])[N:26]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)[N:27]=[C:17]3[C:16]=2[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.CCN(CC)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:34][C:31]1[CH:32]=[CH:33][C:28]([N:26]2[C:25](=[O:35])[N:18]3[C:19](=[O:24])[NH:20][C:21]4[CH:22]=[CH:23][C:14](/[CH:3]=[CH:2]/[C:1]([O:5][CH2:6][C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=5)=[O:4])=[CH:15][C:16]=4[C:17]3=[N:27]2)=[CH:29][CH:30]=1
Reactant: C=CC(=O)OCc1ccccc1
Reactant: Cc1ccc(-n2nc3c4cc(Br)ccc4[nH]c(=O)n3c2=O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nc3c4cc(/C=C/C(=O)OCc5ccccc5)ccc4[nH]c(=O)n3c2=O)cc1
Temperature: 120 °C
Reaction time: 15 h
Yield: 46.8 %

Procedure:
To a stirred solution of benzyl acrylate (44 μg, 0.274 mmol) and 8a (50.6 mg, 0.137 mmol) in a mixture of 8 mL of DMF and 4 mL of NEt3, was added Pd(OAc)2 (3.06 mg, 13.7 mmol) and triphenylphosphine (7.14 mg, 27.4 μmol) in a seal tube. The tube was sealed under argon and the mixture was stirred at 120° C. for 15 h. The mixture was cooled and concentrated to dryness in vacuo and the crude product was precipitated from acetone to give 17 as a white solid (29 mg, 47%). mp: 242° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH2:17][O:18][CH2:19][C:20]3([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[CH:10]=2)=[CH:5][CH:4]=1)#[N:2].CO>ClCCl.FC(F)(F)C(O)=O>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][C:11]=1[CH2:17][O:18][CH2:19][C:20]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1
Reactant: COc1ccc(-c2ccc(C#N)cc2)cc1COCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(-c2ccc(C#N)cc2)cc1COCC1(c2ccccc2)CCNCC1
Reaction time: 0.75 h

Procedure:
tert-Butyl 4-(((4′-cyano-4-methoxybiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (47 mg, 0.092 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1 mL). The reaction was stirred for 45 min and concentrated. The residue was dissolved in methanol and loaded onto an strong cation exchange cartridge. The cartridge was flushed with plenty of methanol which was discarded. The product was then eluted using 2 M ammonia in methanol. The solvent was evaporated to give 34 mg (90%) as a colorless oil. Retention time: 2.20 min. (Phenomenex C18 3.0×50 mm, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA, Gradient time=3 min., Flow rate=4 mL/min.) Mass spec.: 413.39 (MH)+. Accurate mass spec.: m/z 413.2245 [MH]+, Δ=3.9 ppm.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl:23][C:24]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])=[O:36])=[CH:29][C:25]=1[C:26]([OH:28])=O.[Br:41][C:42]1[CH:47]=[CH:46][C:45]([NH:48][C:49](=[O:58])[C:50]2[CH:55]=[C:54]([NH2:56])[CH:53]=[CH:52][C:51]=2[Cl:57])=[CH:44][CH:43]=1>C1COCC1>[Cl:57][C:51]1[CH:52]=[CH:53][C:54]([NH:56][C:26](=[O:28])[C:25]2[CH:29]=[C:30]([CH2:33][NH:34][C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])=[O:36])[CH:31]=[CH:32][C:24]=2[Cl:23])=[CH:55][C:50]=1[C:49]([NH:48][C:45]1[CH:46]=[CH:47][C:42]([Br:41])=[CH:43][CH:44]=1)=[O:58]
Reactant: Nc1ccc(Cl)c(C(=O)Nc2ccc(Br)cc2)c1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2ccc(Cl)c(C(=O)Nc3ccc(Br)cc3)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of TBTU (108 mg, 0.338 mmol), TEA (0.128 mL), 2-chloro-5-(tert-butylcarbonylamino)methyl-benzoic acid (83 mg, 0.31 mmol) and 5 mL THF was stirred for 15 min at rt. Then N-(4-bromophenyl)-2-chloro-5-amino-benzoic acid amide (100 mg, 0.31 mmol, prepared analogously to 2d/2e) was added and it was stirred for 3 h at rt and for additional 3 h at reflux. The mixture was concentrated i.vac., EtOAc was added and the organic phase was washed with 1M NaOH, water, 2M aq. HCl-solution, water and brine and dried with Na2SO4. The crude mixture was concentrated i.vac. and purified by chromatography (silica gel, petrol ether/EtOAc 60/40→55/45) to furnish the title compound.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]([O:13][C:14]1[C:22]3[N:21]=[C:20]([CH3:23])[NH:19][C:18]=3[CH:17]=[C:16]([C:24]([OH:26])=O)[CH:15]=1)[CH2:5][CH2:6][O:7]2.[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][NH:31][CH3:32]>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]([O:13][C:14]1[C:22]3[N:21]=[C:20]([CH3:23])[NH:19][C:18]=3[CH:17]=[C:16]([C:24]([N:31]([CH2:30][CH2:29][N:28]([CH3:33])[CH3:27])[CH3:32])=[O:26])[CH:15]=1)[CH2:5][CH2:6][O:7]2
Reactant: CNCCN(C)C
Reactant: Cc1nc2c(OC3CCOc4cc(F)cc(F)c43)cc(C(=O)O)cc2[nH]1
Product: Cc1nc2c(OC3CCOc4cc(F)cc(F)c43)cc(C(=O)N(C)CCN(C)C)cc2[nH]1
Yield: 13 %

Procedure:
The title compound was prepared as a white solid (10 mg, 13% yield for 3 steps) from 4-[(5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-2-methyl-1H-benzimidazole-6-carboxylic acid (100 mg, crude, STEP 4 in Example 4) and N,N,N′-trimethyl-1,2-ethanediamine (45 mg, 0.44 mmol) by the same manner in STEP 5 of Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[C:11](O)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:11]1[C:10]([N+:15]([O-:17])=[O:16])=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:13][N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cc(-c2ccc(Br)cc2)cnc1O
Agent: O=C([O-])O
Agent: [Na+]
Product: O=[N+]([O-])c1cc(-c2ccc(Br)cc2)cnc1Cl
Temperature: 120 °C

Procedure:
A mixture of 10.2 g of 5-(4-bromphenyl)-2-hydroxy-3-nitropyridine (starting material H4) and 40 ml of phosphorous oxychloride is heated under reflux to 120° C. for 3 hours. After cooling the mixture is carefully added to ice/water, then neutralized with sodium hydrogencarbonate and extracted three times with ethyl acetate. The combined organic phases are evaporated to dryness and the residue is chromatographed on a silica gel column (ethyl acetate/petroleum ether 1:12). Concentration of the chromatographically pure fractions gives 1.52 g of the title compound as yellow crystals of m.p. 116–117° C. The mass spectrum shows the molecular peak M+ at 314 Da.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[S-2].[Na+].[Na+]>>[CH:1]1[CH:2]=[CH:3][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Nc2ccccc2)cc1
Agent: [Na+]
Agent: [S-2]
Product: Nc1ccc(Nc2ccccc2)cc1

Procedure:
formanilide method, where formic acid and aniline are used as starting materials to prepare formanilide, which in turn reacts with p-nitro-chlorobenzene in the presence of an acid-binding agent such as potassium carbonate, to produce 4-nitrodiphenylamine, and then, 4-nitrodiphenylamine is reduced by sodium sulfide to form 4-aminodiphenylamine;
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([C:21](=[O:23])[CH3:22])[CH2:9]1)C1C=CC=CC=1.ClC(OCC(Cl)(Cl)Cl)=O>CC#N>[Cl:20][C:15]1[CH:14]=[C:13]([CH:11]2[CH2:12][NH:8][CH2:9][CH:10]2[C:21](=[O:23])[CH3:22])[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: CC(=O)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(=O)C1CNCC1c1ccc(Cl)c(Cl)c1
Reaction time: 3 h
Yield: 63.2 %

Procedure:
To a solution of 1-[(3SR,4RS)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanone 4.00 g (9.20 mmol) dissolved in CH3CN (50 mL) was added 2.48 mL (18.40 mmol) of 2,2,2-trichloroethyl chloroformate and stirring was continued for 3 hours at RT. Volatiles were removed under vacuo, and the residue was dissolved in AcOH (30 mL) before a total of 1.5 g of Zn dust was added portion wise. After three hours at RT, the reaction mixture was filtered on celite, the solvent removed under vacuo, followed by extraction with EtOAc/aq. NaHCO3 (basic pH). The organic phases were dried on Na2SO4 and column chromatography (SiO2, CH2Cl2/MeOH 9:1 to 8:2) yielded the title compound (1.50 g, 63%) as a colorless oil. ES-MS m/e: 258.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1.O.NN>CO.[Ni]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[O:9][C:10]1[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(Oc2c(F)cccc2F)cc1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1ccc(Oc2c(F)cccc2F)cc1
Reaction time: 0.25 h
Yield: 90.8 %

Procedure:
Into a 500 mL, 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of 1,3-difluoro-2-(4-nitrophenoxy)benzene (20 g, 79.62 mmol, 1.00 equiv) in methanol (200 mL), Raney Nickel (2 g). A solution of hydrazine hydrate (12.67 g) in methanol (50 mL) was added dropwise with stirring in 15 min. The resulting solution was stirred for 12 h at 25° C., then filtrated and the filtrate was concentrated under vacuum. The residue was diluted with 200 mL of ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate and concentrated under vacuum to give 16 g (91%) of 4-(2,6-difluorophenoxy)aniline as a black oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[CH3:27][C:28]1([CH3:40])[CH2:33][CH:32]([NH:34][C:35]2[NH:39][CH:38]=[N:37][N:36]=2)[CH2:31][CH2:30][O:29]1>>[CH3:27][C:28]1([CH3:40])[CH2:33][CH:32]([N:34]2[C:17](=[O:18])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:22]([CH2:23][CH2:24][CH3:25])[N:36]3[N:37]=[CH:38][N:39]=[C:35]23)[CH2:31][CH2:30][O:29]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Reactant: CC1(C)CC(Nc2nnc[nH]2)CCO1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOC(C)(C)C2)c2ncnn12
Temperature: 250 °C
Reaction time: 0.33 h
Yield: 66.8 %

Procedure:
A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (0.89 g) and N-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine (0.25 g) was stirred at 250° C. for 20 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.41 g, 67%).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8]([NH:12]C(=O)C)=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.[OH-].[Na+]>Cl>[CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8]([NH2:12])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: CC(=O)Nc1ccc2c(c1)OCCC2(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)CCOc2cc(N)ccc21
Temperature: 25 °C
Yield: 91 %

Procedure:
A mixture of N-(4,4-dimethyl-chroman-7-yl)-acetamide (1.35 g, 6.2 mmol) in 20% HCl solution (30 mL) was heated at reflux for 3 h and then cooled to room temperature. The reaction mixture was basified with 10% aq. NaOH to pH 8 and extracted with EtOAc (30×3 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated to give 3,4-dihydro-4,4-dimethyl-2H-chromen-7-amine (C-5) (1 g, 92%). 1H NMR (DMSO-d6) δ 6.87 (d, J=8.4 Hz, 1H), 6.07 (dd, J=8.4, 2.4 Hz, 1H), 5.87 (d, J=2.4 Hz, 1H), 4.75 (s, 2H), 3.99 (t, J=5.4 Hz, 2H), 1.64 (t, J=5.1 Hz, 2H), 1.15 (s, 6H); ESI-MS 178.1 m/z (MH+).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]#[N:12])[C:6]([O:8]CC)=[O:7])C.[CH2:13]([O:15][CH:16]([O:20][CH2:21][CH3:22])[CH2:17][NH:18][NH2:19])[CH3:14]>C(O)C.O>[CH2:13]([O:15][CH:16]([O:20][CH2:21][CH3:22])[CH2:17][N:18]1[C:11]([NH2:12])=[C:5]([C:6]([OH:8])=[O:7])[CH:4]=[N:19]1)[CH3:14]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: CCOC(CNN)OCC
Solvent: O
Solvent: CCO
Product: CCOC(Cn1ncc(C(=O)O)c1N)OCC
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 27.6 %

Procedure:
To a suspension of ethyl ethoxymethylenecyanoacetate (21.7 g) in ethanol (65 ml) was added dropwise a solution of hydrazinoacetaldehyde diethyl acetal (19 g) in water (19 ml) under ice-cooling. The mixture was stirred at 80° C. for 1.5 hours and evaporated to remove ethanol. To the residue was 4N sodium hydroxide (64 ml), and the mixture was refluxed for 1 hour. The mixture was adjusted to pH 3.5 with concentrated hydrochloric acid at 10°-20° C., and the resulting precipitate was collected by filtration to give 1-(2,2-diethoxyethyl)-4-carboxy-5-aminopyrazole (8.60 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][OH:11].Cl[C:13]1[CH:23]=[C:17]2[N:18]([CH3:22])[CH2:19][CH2:20][CH2:21][N:16]2[C:15](=[O:24])[N:14]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:13]1[CH:23]=[C:17]2[N:18]([CH3:22])[CH2:19][CH2:20][CH2:21][N:16]2[C:15](=[O:24])[N:14]=1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCCc1ccc(F)cc1F
Product: CN1CCCn2c1cc(OCCc1ccc(F)cc1F)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E11 starting from 2-(2,4-difluorophenyl)ethanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>O>[Cl:8][C:7]1[C:2]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: C1COCCN1
Reactant: Clc1nccnc1Cl
Solvent: O
Product: Clc1nccnc1N1CCOCC1

Procedure:
149 g of 2,3-dichloropyrazine, 300 g of morpholine and 400 ml of water are stirred for 16 hours at 40° C. The reaction mixture is then extracted by shaking with ether. The ether extracts are washed with water until neutral, dried over sodium sulphate and evaporated in a waterpump vacuum. The residue is distilled in a waterpump vacuum. 2-Chloro-3-morpholinyl-pyrazine, boiling point 162°-165° C./15 mm Hg, is thus obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:21][O:20]2)=[C:15]([F:22])[CH:14]=1)(=[O:12])=[O:11].[CH3:27][C:28]1([NH2:32])[CH2:31][O:30][CH2:29]1>C(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]([OH:20])[CH2:21][NH:32][C:28]2([CH3:27])[CH2:31][O:30][CH2:29]2)=[C:15]([F:22])[CH:14]=1)(=[O:12])=[O:11]
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C3CO3)c(F)c2)c(C)c1
Reactant: CC1(N)COC1
Solvent: CCO
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C(O)CNC3(C)COC3)c(F)c2)c(C)c1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a stirred solution of N-(2,4-dimethylphenyl)-3-fluoro-N-isobutyl-4-(oxiran-2-yl)benzenesulfonamide (20 mg, 0.053 mmol) in ethanol at 25° C. was added 3-methyloxetan-3-amine (5.08 mg, 0.058 mmol). The reaction mixture was then stirred at 50° C. for 18 hours. Another portion of 3-methyloxetan-3-amine (5.08 mg, 0.058 mmol) was then added and the reaction stirred for a further 8 hours at 50° C. The reaction mixture was concentrated in vacuo and purified by mass directed autoprep (ammonium carbonate modifier). The relevant fractions were concentrated under a stream of nitrogen to give the required product, 11.2 mg. LCMS [LCMS2] Rt 1.25 min, m/z (ES+) 465 (M+H).
Reaction SMILES: [CH3:1][CH2:2]O.[CH3:4][CH2:5]OC(C)=O.CCO.CC(O)=O.O.[CH:18]1[C:23]([I:24])=[C:22]([O:25][C:26]2[CH:31]=[C:30]([I:32])[C:29]([OH:33])=[C:28]([I:34])[CH:27]=2)[C:21]([I:35])=[CH:20][C:19]=1[CH2:36][C@H:37]([NH2:41])[C:38]([OH:40])=[O:39]>O.CS(C)=O>[CH2:4]([O:39][C:38](=[O:40])[CH:37]([NH:41][CH2:1][CH3:2])[CH2:36][C:19]1[CH:20]=[C:21]([I:35])[C:22]([O:25][C:26]2[CH:27]=[C:28]([I:34])[C:29]([OH:33])=[C:30]([I:32])[CH:31]=2)=[C:23]([I:24])[CH:18]=1)[CH3:5]
Reactant: N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O
Reactant: CCOC(C)=O
Reactant: CCO
Solvent: CC(=O)O
Solvent: O
Solvent: CS(C)=O
Product: CCNC(Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)OCC

Procedure:
Yield: 50%; off-white solid; recrist. solvt.: EtOH; TLC: Rf=0.43 (EtOAc/EtOH 9/1); RPTLC: Rf=0.43 (AcOH/H2O 8/2); mp=136° C.; IR (υ cm−1): 1730 (CO); NMR (DMSO-d6) δ (ppm): 7.79 (s, 2H, ArH), 7.14 (s, 2H, ArH), 4.06-4.02 (m, 2H, CH2), 3.93-3.89 (q, J 7.0 Hz, 2H, CH2), 3.59-3.56 (t, J=7.0 Hz, 1H, CH), 2.80-2.77 (m, 2H, CH2), 1.88 (br, 1H, NH), 1.41-1.39 (t, J=7.0 Hz, 3H, CH3), 1.15-1.12 (t, J=7.0 Hz, 3H, CH3); MS (ESI+) m/z 911.7 [(M+DMSO)+, 100], 833.7 [(M+H)+, 75]; Anal. Calcd. for C19H19I4NO4: C, 27.40; H 2.30; N, 1.68. Found: C, 27.54; H, 1.94; N, 1.66. Solubility 10−3 M in water after preparing a solution at 10−1 M in DMSO. It is noteworthy that if a suspension of L-T4 is prepared overnight, the yield can be increased.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:37])[C:7]=1[CH:8]=[C:9]([O:28][C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:10]1[C:18]2[C:17]3[CH:19]=[C:20]([N+:23]([O-])=O)[CH:21]=[CH:22][C:16]=3[O:15][C:14]=2[C:13]([O:26][CH3:27])=[CH:12][CH:11]=1.C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>C(Cl)Cl.O.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:37])[C:7]=1[CH:8]=[C:9]([O:28][C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:10]1[C:18]2[C:17]3[CH:19]=[C:20]([NH:23][S:46]([CH3:45])(=[O:48])=[O:47])[CH:21]=[CH:22][C:16]=3[O:15][C:14]=2[C:13]([O:26][CH3:27])=[CH:12][CH:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C(=Cc2c(Cl)cncc2Cl)OC(=O)c2ccccc2)c2c1oc1ccc([N+](=O)[O-])cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=Cc2c(Cl)cncc2Cl)OC(=O)c2ccccc2)c2c1oc1ccc(NS(C)(=O)=O)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 25.9 %

Procedure:
Crude benzoic acid 2-(3,5-dichloro-pyridin-4-yl)-1-(4-methoxy-8-amino-dibenzofuran-1-yl)-vinyl ester (1.17 g, obtained as described in Example 8 starting from 1.68 g of benzoic acid 2-(3,5-dichloro-pyridin-4-yl)-1-(4-methoxy-8-nitro-dibenzofuran-1-yl)-vinyl ester) is dissolved in dry DCM (5 mL) under nitrogen atmosphere. The solution is cooled to 0° C. and triethylamine (0.390 mL, 2.80 mmoles) and methanesulphonyl chloride (0.220 mL, 2.83 mmoles) are added sequentially dropwise. The resulting solution is stirred at room temperature for 1 hour. The mixture is diluted with water (2.5 mL) and saturated NaHCO3 solution (10 mL) and extracted with DCM; the combined organic layers are dried over Na2SO4 and evaporated to dryness. The crude is purified by preparative HPLC to yield 330 mg of pure product as a white solid.
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[C:15]1([CH2:21][C:22](O)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C=O)C>[C:1]([C:5]1[C:6]([NH:14][C:22](=[O:23])[CH2:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)Cc1ccccc1
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)(C)c1c(NC(=O)Cc2ccccc2)nn2cccnc12
Yield: 72.9 %

Procedure:
A mixture from Example 105B (103.8 mg, 0.55 mmol), phenylacetic acid (138.6 mg, 1.02 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCL (206.7 mg, 1.08 mmol) in pyridine (1.5 mL) and DMF (1.5 mL) was stirred at ambient temperature for 5 hours. The mixture was concentrated. Purification by reverse phase HPLC afforded 123.7 mg (74%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.39 (s, 9H), 3.63 (s, 2H), 6.99 (dd, J=7.1, 4.1 Hz, 1H), 7.23-7.34 (m, 5H), 8.48 (dd, J=4.1, 1.7 Hz, 1H), 8.91 (dd, J=7.1, 1.7 Hz, 1H), 9.93 (s, 1H); MS (DCI) m/z 309 (M+H)+.